medigraphic.com
ISSN 3061-7774 (Digital)
ISSN 1870-7203 (Impreso)
Órgano Oficial del Hospital Ángeles Health System

2026, Número 4

<< Anterior Siguiente >>

Acta Med 2026; 24 (4)


Acuaporina-4 y el sistema glinfático: claves en el desarrollo del Alzheimer

Ramírez PEU, Hernández LJL, López NM

Idioma: Español
Referencias bibliográficas: 43
Paginas: 427-432
Archivo PDF: 878.71 Kb.


RESUMEN

La enfermedad de Alzheimer (EA) representa la causa más frecuente de demencia a nivel mundial. Existen diversos procesos fisiopatológicos propuestos para el desarrollo de este desorden neurodegenerativo, como la acumulación de depósitos extracelulares de proteínas como la β-amiloide (Aβ) y formas intracelulares hiperfosforiladas de Tau. Este proceso promueve cambios conductuales, así como deterioro cognitivo y funcional progresivo. Recientemente, el sistema glinfático (SG) ha cobrado relevancia debido a la función reguladora de metabolitos cerebrales y a la facilitación de depuración de estos productos neurotóxicos. Es por ello que esta investigación centra su atención en aquellos factores genéticos y físicos que afectan a este sistema para promover el desarrollo de posibles intervenciones terapéuticas y preventivas para el desarrollo de EA.


REFERENCIAS (EN ESTE ARTÍCULO)

  1. Rasmussen MK, Mestre H, Nedergaard M. The glymphatic pathwayin neurological disorders. Lancet Neurol. 2018; 17 (11): 1016-1024.doi: 10.1016/s1474-4422(18)30318-1.

  2. Benveniste H, Liu X, Koundal S, Sanggaard S, Lee H, Wardlaw J. Theglymphatic system and waste clearance with brain aging: a review.Gerontology. 2019; 65 (2): 106-119. doi: 10.1159/000490349

  3. Chong PLH, Garic D, Shen MD, Lundgaard I, Schwichtenberg AJ.Sleep, cerebrospinal fluid, and the glymphatic system: a systematicreview. Sleep Med Rev. 2022; 61: 101572. doi: 10.1016/j.smrv.2021.101572.

  4. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JDet al. Structural and functional features of central nervous systemlymphatic vessels. Nature. 2015; 523 (7560): 337-341. doi: 10.1038/nature14432.

  5. Gao Y, Liu K, Zhu J. Glymphatic system: an emerging therapeuticapproach for neurological disorders. Front Mol Neurosci. 2023; 16:1138769. doi: 10.3389/fnmol.2023.1138769.

  6. Silverthorn DU. Fisiología Humana Integrada. 8va. Ed. Panamericana;2019. p. 294.

  7. Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar Met al. A dural lymphatic vascular system that drains brain interstitialfluid and macromolecules. J Exp Med. 2015; 212 (7): 991-999. doi:10.1084/jem.20142290.

  8. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al.A paravascular pathway facilitates CSF flow through the brainparenchyma and the clearance of interstitial solutes, includingamyloid β. Sci Transl Med. 2012; 4 (147): 147ra111. doi: 10.1126/scitranslmed.3003748.

  9. Hablitz LM, Nedergaard M. The glymphatic system: a novelcomponent of fundamental neurobiology. J Neurosci. 2021; 41 (37):7698-7711. doi: 10.1523/JNEUROSCI.0619-21.2021.

  10. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M et al. Sleepdrives metabolite clearance from the adult brain. Science. 2013; 342(6156): 373-377. doi: 10.1126/science.1241224.

  11. Jessen NA, Munk ASF, Lundgaard I, Nedergaard M. The glymphaticsystem: a beginner’s guide. Neurochem Res. 2015; 40 (12): 2583-2599. doi: 10.1007/s11064-015-1581-6.

  12. Benveniste H, Heerdt PM, Fontes M, Rothman DL, Volkow ND.Glymphatic system function in relation to anesthesia and sleepstates. Anesth Analg. 2019; 128 (4): 747-758. doi: 10.1213/ane.0000000000004069.

  13. Thrane VR, Thrane AS, Plog BA, Thiyagarajan M, Iliff JJ, Deane R et al.Paravascular microcirculation facilitates rapid lipid transport and astrocytesignaling in the brain. Sci Rep. 2013; 3: 2582. doi: 10.1038/srep02582.

  14. Maneshi MM, Maki B, Gnanasambandam R, Belin S, PopescuGK, Sachs F, et al. Mechanical stress activates NMDA receptors inthe absence of agonists. Sci Rep. 2017; 7: 39610. doi: 10.1038/srep39610.

  15. Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J et al. Deletion ofaquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation andmemory deficits. Mol Neurodegener. 2015; 10: 58. doi: 10.1186/s13024-015-0056-1.

  16. Martínez-Cogollo JA, García-Ávila CA, Sobrino-Mejía FE. Sistemaglinfático: aspectos anatómicos, fisiológicos e implicaciones clínicas.Acta Neurol Colomb. 2023; 39 (2). doi: 10.22379/anc.v39i2.835.

  17. Raper D, Louveau A, Kipnis J. How do meningeal lymphatic vesselsdrain the CNS? Trends Neurosci. 2016; 39 (9): 581-586. doi:10.1016/j.tins.2016.07.001.

  18. Kiviniemi V, Wang X, Korhonen V, Keinanen T, Tuovinen T, Autio J etal. Ultra-fast magnetic resonance encephalography of physiologicalbrain activity - Glymphatic pulsation mechanisms? J Cereb Blood FlowMetab. 2016; 36 (6): 1033-1045. doi: 10.1177/0271678X15622047.

  19. Armstrong RA. Risk factors for Alzheimer’s disease. Folia Neuropathol.

  20. 2019; 57 (2): 87-105. doi: 10.5114/fn.2019.85929.20. Wu Z, Wang ZH, Liu X, Zhang Z, Gu X, Yu SP et al. Traumatic braininjury triggers APP and Tau cleavage by delta-secretase, mediatingAlzheimer’s disease pathology. Prog Neurobiol. 2020; 185 (101730):101730. doi: 10.1016/j.pneurobio.2019.101730.

  21. Gómez-Virgilio L, Reyes-Gutiérrez GS, Silva-Lucero M del C, López-Toledo G, Cárdenas-Aguayo M del C. Etiología, factores de riesgo,tratamientos y situación actual de la enfermedad de Alzheimer enMéxico. Gac Med Mex. 2022; 158 (4): 235-241. doi: 10.24875/gmm.22000023.

  22. Gottesman RF, Lutsey PL, Benveniste H, Brown DL, Full KM, Lee J-Met al. Impact of sleep disorders and disturbed sleep on brain health:A scientific statement from the American heart association. Stroke.2024; 55 (3): e61-e76. doi: 10.1161/STR.0000000000000453.

  23. Wu Z, Chen C, Kang SS, Liu X, Gu X, Yu SP et al. Neurotrophicsignaling deficiency exacerbates environmental risks for Alzheimer’sdisease pathogenesis. Proc Natl Acad Sci U S A. 2021; 118 (25):e2100986118. doi: 10.1073/pnas.2100986118.

  24. Iliff JJ, Chen MJ, Plog BA, Zeppenfeld DM, Soltero M, Yang L et al.Impairment of glymphatic pathway function promotes tau pathologyafter traumatic brain injury. J Neurosci. 2014; 34 (49): 16180-16193.doi: 10.1523/JNEUROSCI.3020-14.2014.

  25. Iliff JJ, Wang M, Zeppenfeld DM, Deane, Rashid. Cerebral arterialpulsation drives paravascular CSF-interstitial fluid exchange in themurine brain. J Neuroscien. 2013; 33 (46): 18190-18199.

  26. Sun YY, Wang Z, Huang HC. Roles of ApoE4 on the pathogenesis inAlzheimer’s disease and the potential therapeutic approaches. CellMol Neurobiol. 2023; 43 (7): 3115-3136. doi: 10.1007/s10571-023-01365-1.

  27. Zollo A, Allen Z, Rasmussen HF, Iannuzzi F, Shi Y, Larsen A, Maier TJ,Matrone C. Sortilin-Related Receptor Expression in Human NeuralStem Cells Derived from Alzheimer’s Disease Patients Carrying theAPOE Epsilon 4 Allele. Neural Plast. 2017; 2017: 1892612. doi:10.1155/2017/1892612.

  28. Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC. ApoE inAlzheimer’s disease: pathophysiology and therapeutic strategies. MolNeurodegener. 2022; 17 (1): 72. doi: 10.1186/s13024-022-00574-4.

  29. Bentley NM, Ladu MJ, Rajan C, Getz GS, Reardon CA. ApolipoproteinE structural requirements for the formation of SDS-stable complexeswith beta-amyloid-(1-40): the role of salt bridges. Biochem J. 2002;366 (Pt 1): 273-279. doi: 10.1042/BJ20020207.

  30. Tachibana M, Holm M-L, Liu C-C, Shinohara M, Aikawa T, Oue H et al.APOE4-mediated amyloid-β pathology depends on its neuronal receptorLRP1. J Clin Invest. 2019; 129 (3): 1272-1277. doi: 10.1172/JCI124853.

  31. Kara E, Marks JD, Roe AD, Commins C, Fan Z, Calvo-Rodriguez Met al. A flow cytometry-based in vitro assay reveals that formation ofapolipoprotein E (ApoE)-amyloid beta complexes depends on ApoEisoform and cell type. J Biol Chem. 2018; 293 (34): 13247-13256.doi: 10.1074/jbc.RA117.001388.

  32. Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, BanerjiAO et al. Apolipoprotein E, especially apolipoprotein E4, increasesthe oligomerization of amyloid β peptide. J Neurosci. 2012; 32 (43):15181-15192. doi: 10.1523/JNEUROSCI.1542-12.2012.

  33. Maroli N. Aquaporin-4 mediated aggregation of Alzheimer’s amyloidβ-peptide. ACS Chem Neurosci. 2023; 14 (15): 2683-2698. doi:10.1021/acschemneuro.3c00233.

  34. Rosu GC, Catalin B, Balseanu TA, Laurentiu M, Claudiu M, Kumar-Singh S et al. Inhibition of aquaporin 4 decreases amyloid Aβ40drainage around cerebral vessels. Mol Neurobiol. 2020; 57 (11):4720-4734. doi: 10.1007/s12035-020-02044-8.

  35. Manescu MD, Catalin B, Baldea I, Mateescu VO, Rosu GC, BobocIKS et al. Aquaporin 4 modulation drives amyloid burden andcognitive abilities in an APPPS1 mouse model of Alzheimer’s disease.Alzheimers Dement. 2025; 21 (5): e70164. doi: 10.1002/alz.70164.

  36. Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, et al. SingleApp knock-in mouse models of Alzheimer’s disease. Nat Neurosci.2014; 17 (5): 661-663. doi: 10.1038/nn.3697.

  37. Van Giau V, Bagyinszky E, Youn YC, An SSA, Kim S. APP, PSEN1, andPSEN2 mutations in Asian patients with early-onset Alzheimer disease.Int J Mol Sci. 2019; 20 (19): 4757. doi: 10.3390/ijms20194757.

  38. Gao Y, Ren R-J, Zhong Z-L, Dammer E, Zhao Q-H, Shan S et al.Mutation profile of APP, PSEN1, and PSEN2 in Chinese familialAlzheimer’s disease. Neurobiol Aging. 2019; 77: 154-157. doi:10.1016/j.neurobiolaging.2019.01.018.

  39. Wolfe MS. Presenilin, γ-secretase, and the search for pathogenictriggers of Alzheimer’s disease. Biochemistry. 2025; 64 (8): 1662-1672. doi: 10.1021/acs.biochem.4c00830.

  40. Trambauer J, Fukumori A, Steiner H. Pathogenic Aβ generationin familial Alzheimer’s disease: novel mechanistic insights andtherapeutic implications. Curr Opin Neurobiol. 2020; 61: 73-81.doi: 10.1016/j.conb.2020.01.011.

  41. Mehra R, Kepp KP. Computational analysis of Alzheimer-causingmutations in amyloid precursor protein and presenilin 1. Arch BiochemBiophys. 2019; 678: 108168. doi: 10.1016/j.abb.2019.108168.

  42. Fernandez MA, Klutkowski JA, Freret T, Wolfe MS. Alzheimerpresenilin-1 mutations dramatically reduce trimming of long amyloidβ-peptides (Aβ) by γ-secretase to increase 42-to-40-residue Aβ. J BiolChem. 2014; 289 (45): 31043-31052. doi: 10.1074/jbc.M114.581165.

  43. Kabir MT, Uddin MS, Setu JR, Ashraf GM, Bin-Jumah MN, Abdel-Daim MM. Exploring the role of PSEN mutations in the pathogenesisof Alzheimer’s disease. Neurotox Res. 2020; 38 (4): 833-849. doi:10.1007/s12640-020-00232-x.




2020     |     www.medigraphic.com